Inflammation is a complex stereotypical reaction of the body expressing the response to damage of its cells and vascularized tissues. Prostaglandins are primary contributors to conditions of inflammation, pain and fever. Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the bio-synthesis of prostaglandins. (D. F. Steiner and J. L. Clark, Proc. Natl. Acad. Sci., U.S.A., 60, 622 (1968)). Prostaglandins are biosynthesized with arachidonic acid serving as precursor for an entire cascade of acidic lipids. The biosynthetic reaction for the formation of prostaglandins from arachidonic acids are catalyzed by multienzyme complex commonly referred to as the cyclooxygenase (COX) pathway, COX-1 and COX-2. The reaction proceeds in two stages. In the first stage, the substrate arachidonic acid is transformed into prostaglandins endoperoxide (PGG2 and PGH2) and in the second stage PGG2 and PGH2 are rearranged to form various prostaglandins such as PGD2, PGE2 and PGI2. NSAIDs inhibit the cyclooxygenase step and prevents formation of prostaglandins endoperoxide (PGG2 and PGH2) and thromboxane A2 and other prostaglandins and consequently reduces the signs and symptoms of inflammation (K. Brune, M. Glatt. And P Graf, Gen Pharmacology. 7, 28 (1976). Chronic use of these drugs is associated with side effects such as gastrointestinal irritation (mucosal damage, bleeding) and also at the renal level, thereby limiting their therapeutic potential. Developing safer NSAIDs as selective COX-2 inhibitors is challenge. Several known selective COX-2 inhibitors are Celecoxib (J. Med. Chem. 1997, 40(9), 1347-1365), Rofecoxib (Bioorg. Med. Chem. Lett. 1999, 9, 1773-1778), Valdecoxib (J. Med. Chem. 2000, 43(5), 775-777), Parecoxib Na (J. Med. Chem. 2000, 43(9), 1661-1663) and Etoricoxib (J. Pharmacology. Exp. Ther. 2002, 296 (2), 558-566).
However, some of selective COX-2 inhibitors exhibit similar side effects such as edema, hypertension as of conventional NSAIDs and the potentially increased risk of thrombosis (N. Eng. J. Med. 2000, 343:1520-1528). Gastrointestinal safety of NSAIDs is a major limitation to the use of this class of drugs. There is an increased concern about their cardiovascular adverse effects. The present invention is aimed at inventing novel NSAID compounds useful for the treatment of various types of pain and inflammatory disorder, the process for the preparation of these compounds that have substantially reduced side effects. WO2002079145 and WO01/19788 teaches b enzamide compound in its main claim and its use for the regulation of homeostasis, and for prevention and treatment of thrombus formation and other pathological processes in the vasculature induced by thrombin such as restenosis and inflammation. The compounds have benzamide as essential structural component.
WO9938829 teach novel tricyclic compounds with variable substitution at para position used as an immunosuppressant, an anti allergic agent or a suppressant of the Immunoglobulin E production.
In EP465368 a series of imidazole biphenyl compounds are described as angiotensin II inhibitor and also describes uses in the treatment of arterial hypertension, cardiac insufficiencies, renal insufficiencies and in the prevention of post angioplastic reoccurrences of stenosis, treatment of certain gastro intestinal and gynecological disorders, and in particular for a relaxing effect at the level of the uterus. The essence of the invention is use of imidazole biphenyl as anti-hypertensive.
U.S. Pat. Nos. 5,391,732 and 5,527,919 teach novel process for the preparation of imidazole biphenyl derivatives by disclosing use of Suzuki coupling and use of the compounds in the treatment of ischemic conditions.
JP09165378 teaches F18 substituted imidazole biphenyl compounds used as angiotensin II inhibitor.
EP855392 teaches use of imidazole compounds for the treatment or prophylaxis of illnesses caused by ischemic conditions, and also for the production of a medicament for the treatment of impaired respiratory drive. The essence of invention is compound with five membered heterocycles with biphenylsulfonyl substitution with sulfonylcyanamide side chain.
U.S. Pat. No. 6,369,236 teaches use of imidazole biphenyl sulfonyl amide compounds as an intermediate to prepare imidazole biphenyl sulfonyl cynamide compounds.
WO2005051928, WO2005051929, WO2007054965 teach process to prepare tetrazolyl compounds of biphenyl derivatives.
US20040097565 and U.S. Pat. No. 6,833,381 describe the use of heterocyclic compounds having angiotensin II antagonistic activity, e.g. losartan, candesartan as analgesic agent and method of inhibiting tumor necrosis factor-α (TNF-α) activity respectively for treating inflammatory diseases.
Surprisingly, it is observed that a series of novel biphenyl imidazole compounds, in particular substituted biphenyl imidazole compounds of Formula (I) and Formula (II) exhibit excellent anti-inflammatory properties and have utility in the treatment and prevention of inflammation in living bodies, animals and human being. It is also noticed that none of the prior art motivates the person skilled in the art to synthesize compounds specifically disclosed by the present invention and make use of the compounds as described in the present invention.
WO2002079145 and WO01/19788 does not teach use of biphenyl imidazole compounds as anti-inflammatory.
WO9938829 does not teach biphenyl compounds disclosed by present invention such as biphenyl imidazole compounds and nitro substituted imidazole compounds.
Although EP465368 teaches a series of imidazole biphenyl compounds, but it does not describe specifically the compounds as disclosed by the present invention which are structurally different and have anti-inflammatory use.
Though U.S. Pat. Nos. 5,391,732 and 5,527,919 teach novel process for the preparation of imidazole biphenyl derivatives, it does not specifically refer to compounds of the present invention as described by present invention.
Although JP09165378 teaches F18 substituted imidazole biphenyl compounds, it does not teach use of compounds disclosed by present invention for anti-inflammatory applications.
EP855392 neither teach compounds that are taught by present invention nor EP855392 teach use of imidazole compounds for anti-inflammatory applications.
U.S. Pat. No. 6,369,236 although relates to nitro imidazole compounds, it does not teach nitroimidazole substituted compounds as disclosed by present invention nor does it teach use of nitro imidazole compounds for anti-inflammatory applications.
Although WO2005051928, WO2005051929, WO2007054965 teach tetrazolyl compounds, and are silent about nitro imidazole compounds as taught by present invention.
US20040097565 does not teach biphenyl compounds which are the object of the present invention.
Prior art neither specifically teaches the classes of compounds as disclosed by the present invention nor does it motivate the person skilled in the art to prepare the compounds as disclosed by present invention and make use of these compounds for anti-inflammatory applications. Prior art is devoid of teachings related to formulating compositions from the compounds of Formula I and Formula II as disclosed by present invention. Prior art is silent about making use of the compositions containing compounds of Formula I and Formula II for anti-inflammatory applications.